Pediatrics

Neurofibromatosis type-2

OVERVIEW: What every practitioner needs to know

Are you sure your patient has neurofibromatosis type 2? What are the typical findings for this disease?

Neurofibromatosis Type 2 (NF2) is a relatively rare autosomal dominant disorder with an incidence of approximately 1 in 33,000 people. Half of cases are inherited and half are the result of de novo mutations in the NF2 gene and genetic mosaicism may occur. The gene for NF2 is located on the long arm of chromosome 22 (22q12.2). The hallmark feature of NF2 is the growth of bilateral vestibular schwannomas (also known as acoustic neuromas). Other features include meningiomas, schwannomas of other cranial nerves, spinal roots and peripheral nerves, spinal ependymomas and cataracts. Though NF2 has essentially 100% penetrance, there is wide phenotypic variability. The factors modulating phenotypic variability in NF2 are not well understood but likely represent both genetic and environmental factors.

Unlike NF1, the features of NF2 are restricted almost entirely to tumors of the central and peripheral nervous system (particularly schwannomas) with few cutaneous or non-nervous system related abnormalities.

Clinical Diagnostic Criteria

Based on guidelines published in 1997, the clinical diagnosis of NF2 is based on specific clinical criteria. Specifically, NF2 is diagnosed in individuals with one of the following:

Presumptive or probable NF2 is diagnosed in individuals with the following clinical features:

1) Unilateral vestibular schwannomas before the age of 30 AND at least one of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract

OR

2) Multiple meningiomas (2 or more) AND unilateral vestibular schwannomas before the age of 30 OR one of the following: glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract

Clinical Features

NF2 generally presents during young adulthood, most commonly with hearing loss with the development of vestibular schwannomas or with other symptoms secondary to meningiomas or spinal schwannomas. The average age of symptom onset in patients with NF2 is about 20 years, while the average age of diagnosis is at about age 28. Patients who present in childhood tend to present with signs or symptoms from tumors other than vestibular schwannomas and tend to have a more severe phenotype.

Schwannomas are the cardinal feature of NF2. They can arise from any of the cranial nerves though most commonly arise from the vestibular portion of the VIIIth cranial nerve. Schwannomas can also arise in spinal roots or any nerve distal to the spinal cord.

Schwannomas arising at the cerebello-pontine angle, from the vestibular portion of the VIIIth cranial nerve (vestibular schwannomas [VS]) are essentially universal among patients with NF2. VS most commonly present with auditory symptoms. They are typically slow growing and typically cause gradual deterioration in hearing. Balance and other cranial nerve functions may become impaired. Brainstem compression and obstructive hydrocephalus can occur.

Schwannomas arising from the dorsal spinal roots (spinal schwannomas) are present in more than 80% of patients with NF2. Spinal schwannomas are usually small and asymptomatic, though they can become large, causing compression of the spinal cord or adjacent organs. These tumors are radiographically indistinguishable from neurofibromas arising from spinal roots in NF1 patients, frequently taking on the same “dumbbell” appearance.

Peripheral schwannomas can arise from any nerve, superficial or deep, and can cause pain or impaired motor or sensory function. Superficial peripheral schwannomas can manifest as subcutaneous nodules or as raised, well-circumscribed cutaneous lesions, often with some associated skin and hair changes. Though cutaneous schwannomas are seen in up to half of NF2 patients they are generally a relatively minor component of the disorder.

Approximately half of patients with NF2 develop meningiomas. They are typically slow growing and can occur in meninges of the brain or spine. Many of these meningiomas are asymptomatic, though pain and neurologic dysfunction may occur based on tumor size, location and extent of peritumoral edema. Ependymomas and possibly other astrocytomas are also more prevalent in patients with NF2, with estimates of incidence as high as 1 in 3 patients. The vast majority of glial neoplasms seen in NF2 patients are ependymomas. These are usually intramedullary spinal or cauda equina tumors but rarely they may be intracranial.

Visual impairment is common in the NF2 population. Juvenile posterior subcapsular lenticular opacities are common, though are not always symptomatic. Retinal abnormalities, particularly hamartomas are also frequently seen. Corneal injury may occur in patients with facial weakness. Optic nerve and/or orbital meningiomas are also seen in some patients with NF2 and can cause visual impairment.

Patients with NF2 develop few neurologic manifestations other than the direct result of their tumor burden. Patients with NF2 may develop a peripheral neuropathy and hyporeflexia that is not necessarily directly related to the growth of schwannomas. Foot drop is common.

What other disease/condition shares some of these symptoms?

At times, there may be difficulty distinguishing NF2 from several other conditions including sporadic VS, multiple meningioma syndrome, NF1 and, perhaps most importantly schwannomatosis.

Schwannomatosis is a rare form of neurofibromatosis that has only recently been defined. It may affect as many as 1:40,000 people. Similar to people with neurofibromatosis type 2 people with schwannomatosis develop multiple schwannomas on cranial, spinal and peripheral nerves. However, unlike NF2, they do not develop vestibular schwannomas. Additionally, they do not typically develop other types of tumors associated with neurofibromatosis such as meningiomas, ependymomas, neurofibromas or astrocytomas and there does not seem to be any increased risk of developing malignancies.

People with schwannomatosis often have problems with pain. In many patients this is their only symptom. Schwannomatosis is a genetic condition, but unlike NF1 and NF2 it does not have a clear pattern of inheritance and most commonly develops sporadically without a family history of the disorder. In 2007, a candidate gene for schwannomatosis, called INI1 (or SMARCB1), was identified. This gene seems to account for some, but not all cases of Schwannomatosis.

What caused this disease to develop at this time?

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What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of NF2 is typically made on the basis of clinical diagnostic criteria as previously described. However, genetic testing is available and can help clarify the diagnosis in unusual presentations and can be useful for screening pre-symptomatic relatives. Current testing of lymphocyte DNA from non-founder (familial) NF2 patients is about 92% sensitive, but only about 70% in founder (sporadic) NF2 patients. This lack of sensitivity in non-familial cases is likely due to the high prevalence of genetic mosaicism. As such, a positive genetic test can be helpful in confirming the diagnosis, screening other family members, and if possible pre-implantation genetic testing. A negative test result does not rule out NF2 and the diagnosis must be made on the basis of clinical diagnostic criteria.

Would imaging studies be helpful? If so, which ones?

Please see below.

If you are able to confirm that the patient has neurofibromatosis type 2, what treatment should be initiated?

On initial evaluation of persons with NF2, thorough neurologic and ophthalmologic examinations, formal audiologic testing, and a gadolinium enhanced magnetic resonance imaging (MRI) of the brain with thin cuts through internal auditory canals should be performed in most patients. A spinal MRI should be considered if there are signs or symptoms suggestive of myelopathy. Genetic counseling, including consideration of genetic and/or radiologic screening of at risk relatives should also be provided.

For most patients with NF2 yearly evaluations should include a thorough clinical/neurologic exam, audiologic testing, and brain MRI. Serial spine MRIs need only be performed in patients with known large or symptomatic spinal tumors.

Treatment decisions regarding VS in NF2 are quite complex. The decision to treat is highly individualized, based on the degree of hearing loss, size and rate of growth of the tumor, contralateral function, and signs of dysfunction of other cranial nerves or the brainstem. In general, the mainstay of treatment is surgical resection. Small VS (under 1.5cm) generally can be resected with preservation of hearing and facial nerve function. Larger tumors are generally monitored and only resected or debulked when they are showing signs of progression (radiographic and/or clinical). Auditory brainstem implants (ABI) are offered at some centers.

Stereotactic radiosurgery may be used in some circumstances, however, outcome data are mixed and there is concern that individuals with NF2 may have increased risk of secondary malignancy after radiation treatment.

Treatment of other tumors, including peripheral and spinal schwannomas, meningiomas and ependymomas, is generally reserved for progressive symptomatic tumors, and is limited to surgical resection or debulking.

Most patients with NF2 should be encouraged to learn lip reading and/or sign language in anticipation of eventual loss of hearing. Hearing aids may be of some benefit before complete loss of hearing.

Recently, there has been promising preliminary data suggesting that several molecularly targeted therapeutics may hold promise for the treatment of NF2. Most recently, in a retrospective analysis of 10 NF2 patients treated with bevacizumab the majority of patients showed radiographic and/or audiologic improvement. Several clinical trials for treatment of NF2 are currently underway.

What are the adverse effects associated with each treatment option?

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What are the possible outcomes of neurofibromatosis type 2?

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What causes this disease and how frequent is it?

NF2 is an autosomal dominant genetic condition. A mutation in the NF2 gene causes loss of function of the merlin protein. The exact mechanisms by which the loss of merlin function leads to clinical manifestations of NF2 are not yet fully elucidated. Merlin may act as a tumor suppressor in part through interactions with several proteins in pro-oncogenic pathways such as ras. Additionally, merlin may play an important role in contact mediated growth inhibition.

How do these pathogens/genes/exposures cause the disease?

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Other clinical manifestations that might help with diagnosis and management

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What complications might you expect from the disease or treatment of the disease?

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Are additional laboratory studies available; even some that are not widely available?